Corneal and conjunctival lesions are one of the most diagnosed conditions in patients consulting their physician, and one of the major causes of sight loss. These lesions may be of various origins but are mainly due to allergy, infections (bacterial, viral and fungal), dry eye syndrome, surgery and other traumatisms. These lesions are harmful and very painful. Symptoms of these lesions may be dryness, burning and a sandy-gritty eye irritation. Symptoms may also be described as itchy, scratchy, stingy or tired eyes. Other symptoms are ocular pain, redness, a pulling sensation, and pressure behind the eye. The damage to the eye surface increases discomfort and sensitivity to bright light. Ocular surface lesions need to be treated and healed up very rapidly to avoid worsening of the situation and complications such as ulceration, which may lead to loss of visual acuity and blindness in the most severe cases. For the treatment of lesions due to dry eye syndrome, many lubricating solutions and hydrating hydrogels exist. However, these products only relieve the symptoms but do not accelerate the healing process of the lesions. For deeper lesions, there are some vitamin A solutions, which may help in healing up but with limited efficiency. Beside, compositions enhancing mucins secretion may be of interest. Mucins are extracellular proteins (transmembrane or secreted proteins) which provide protective and lubricating effects to epithelial cells, especially those of cornea and conjunctiva. It has been demonstrated that mucins are secreted by goblet and cornea epithelial cell vesicles and discharged on the surface of the conjuctival epithelium of human eyes (Greiner et. al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, 98: 1843-1846 (1980); and Dilly et. al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucus from a Non-Goblet-Cell Source, British Journal of Ophthalmology, 65: 833-842 (1981)).
When addressing the treatment of corneal and conjunctival lesions, an issue is to activate and promote the natural mechanisms of healing such as the cell proliferation and the secretion of growth factors, mucins and glycosyl amino-glycan.
Another issue is to improve/enhance the healing process and to relieve symptoms, associated or not, with dry eye condition.
Xalatan® is, to date, the most prescribed anti-glaucoma medicine in the world. It contains latanoprost, a prostaglandin F2alpha analogue, at a concentration of 0.005%. This product is sold in a multidose bottle of 5 ml preserved by benzalkonium chloride at 0.02%. Even though Xalatan® is very appreciated for the treatment of glaucoma, it has side effects, some of which may be due to the presence of the preservative agent. After a few months of treatment of this chronic life-long disease, Xalatan® eye drops may start to irritate and wound the ocular surface. Thus, people suffering from glaucoma may subsequently suffer from corneal and conjunctival lesions too. Long-term use of this product is also suspected to trigger dry eye condition (Erb et al. 2008; Eamon et Al. J Glaucoma, August 2008). Therefore, the use of preserved medications, including Xalatan®, is not advised for glaucoma patients suffering from ocular surface diseases.
There is an issue for patients having ocular surface conditions, and also suffering from glaucoma, to get an efficient treatment for their glaucoma whereas also treating (and not worsening) their ocular surface lesions or diseases.
US 2005124699 describes the use of topical applications of prostaglandin E for treating or preventing disorders of corneal and/or conjunctival epithelial cells. This patent describes more particularly the use of either prostaglandin E1 or E2, alone, in combination or in combination with an anti-inflammatory drug. Prostaglandins F2alpha are not disclosed nor suggested as a possible treatment for corneal and conjunctival disorders.
Prostaglandins E can be used for the treatment of corneal and conjunctival lesions. However, it is always beneficial for the patient to have alternative treatments in case of allergy or resistance to the treatment.
The Applicant addressed the above-cited technical issues, and formulated a new composition for use in treating corneal and/or conjunctival lesions, wherein the composition comprises a prostaglandin F2alpha analogue or derivative thereof, in a therapeutic amount, preferably in a concentration ranging from 0.0001 to 0.005% w/w of the total composition, said composition being in a form suitable for topical application on the ocular surface and being free of any kind of deleterious preservative.
The composition of the invention was tested in an animal model of ocular surface alteration to evaluate its potential toxicity. As expected, the applicant noticed that the composition of the invention displayed no toxicity sign on the corneal surface, but surprisingly the composition have ocular healing properties. These healing properties are not observed with Xalatan®, even though Xalatan® uses as active agent a prostaglandin (PG) F2 alpha. This is most probably due to the presence of the preservative agent used in Xalatan® that may act as a masking agent for the healing properties of the PG analogue.
The composition of the invention is therefore suitable for the treatment of ocular surface diseases including corneal and conjunctival lesions, more specifically wounds from various origins (surgery, PRK, LASIK, infections, etc.) and dry eye syndrome (from iatrogenic, immunologic or environmental causes).
The composition of the invention has further advantages. For example, prostaglandins F2alpha have been used in ophthalmology for years and their toxicity, side effects and pharmacokinetic profiles are well known. The composition of the invention developed with a prostaglandin F2alpha may be quickly made available to patients thanks to all the knowledge accumulated about these therapeutic agents. As there is an urgent need for a treatment of corneal and conjunctival lesions, the choice of a prostaglandin F2alpha appears appropriate.
Another advantage of the composition is that it may combine various mechanisms of action. In an embodiment of the invention, the composition may be hypoosmotic to correct the effect of dryness. An osmoprotectant such as for example erythritol may be added to the composition to protect corneal cells from osmotic outflow. Thickening and/or moisturizing agents may also be added to exert a lubricating effect and a wetting effect.
In another embodiment, the composition of the invention is isoosmotic.
The prostaglandin may be administered topically either as eye drops or artificial tears; a gel, preferably a viscous gel; a solid insert or an ointment.
The composition may be in the form of a solution, such as for example an aqueous solution, a micellar solution; or in the form of a suspension; or in the form of an anionic or cationic emulsion. According to a preferred embodiment, the composition is a cationic emulsion.
Without willing to be linked by any theory, the Applicant suggests that the effect of prostaglandin F2alpha could be explained according to the following mechanism: prostaglandin F2alpha analogue may activate FP receptor (receptor of prostaglandin F on the cellular surface). This binding may activate secretion of the mucin MUC5AC from the goblet cells, thus increasing the ocular surface hydration and protecting the eye surface (Chung W C, Ryu S H, Sun H, Zeldin D C, Koo J S. CREB mediates prostaglandin F2alpha-induced MUC5AC overexpression. J Immunol. 2009; 182(4):2349-56). The prostaglandin may at the same time increase matrix metalloproteinases (MMP) secretion which favor cell remodelling and cellular shape change during the healing of wounds (Mietz H, Esser J M, Welsandt G, Kociok N, Hueber A, Joussen A, Esser P, Krieglstein G K. Latanoprost stimulates secretion of matrix metalloproteinases in tenon fibroblasts both in vitro and in vivo. Invest Ophthalmol Vis Sci. 2003; 44(12):5182-8.)
The prostaglandin may also improve wound healing via the induction of EGR-1 (early growth response factor-1) (Xu W, Chou C L, Sun H, Fujino H, Chen Q M, Regan J W. FP prostanoid receptor-mediated induction of the expression of early growth response factor-1 by activation of a Ras/Raf/mitogen-activated protein kinase signaling cascade. Mol Pharmacol. 2008; 73(1):111-8.)
The following schemas illustrate the cascade of event consecutive to an exposition to prostaglandin F2alpha: (+) stands for “activation”.
                                          PGF            ⁢                                                  ⁢            2            ⁢                                                  ⁢            alpha                    →                                                    (                +                )                            ⁢                                                          ⁢              FP              ⁢                                                          ⁢              receptor                        →                                          (                +                )                            ⁢                                                          ⁢              PLC                                      ,        PKC        ,                              Ca                          2              +                                ⁢                                          ⁢          signalling                                                                  ⁢                  ↓                      (            +            )                          ⁢                                                                    IP          3                ⁢                                  ⁢        and        ⁢                                  ⁢        DAG                                                          ⁢                  ↓                      (            +            )                    ⁢                                          ↓                      (            +            )                                                  Increases        ⁢                                  ⁢                  Ca                      2            +                          ⁢                                  ⁢        PKC                                ↓                  (          +          )                                                  sPLA          2                ⁢                                  ⁢                  (                      has            ⁢                                                  ⁢            wound            ⁢                                                  ⁢            healing            ⁢                                                  ⁢            activity                    )                                                  PGF          ⁢                                          ⁢          2          ⁢                                          ⁢          alpha                →                                                            (                +                )                            ⁢              EGF                        +            EGFR                    →                                    (              +              )                        ⁢                                                  ⁢            cell            ⁢                                                  ⁢            proliferation                                                  ↓                  (          +          )                                        15        ⁢                  -                ⁢        HETE        ⁢                                  ⁢                  (                      has            ⁢                                                                      ⁢                                                                    ⁢            secretagogue            ⁢                                                  ⁢            activity            ⁢                                                  ⁢            of            ⁢                                                  ⁢            mucins                    )                                        ↓                  (          +          )                                                  LXA          4                ⁢                                  ⁢                  (                      is            ⁢                                                  ⁢            anti            ⁢                          -                        ⁢            inflammatory            ⁢                                                  ⁢            and            ⁢                                                  ⁢            favors            ⁢                                                  ⁢            re            ⁢                          -                        ⁢            epithelization                    )                    
Activation of these cascades may result in the secretion of mucins which contribute significantly to the healing of lesions (Landreville S, Coulombe S, Carrier P, Gelb M H, Guérin S L, Salesse C. Expression of phospholipases A2 and C in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2004 November;45(11):3997-4003; Gronert K. Lipid autacoids in inflammation and injury responses: a matter of privilege. Mol Interv. 2008; 8(1):28-35.)
According to the invention, the Applicant selected as active substance a prostaglandin F2alpha or analogue, and derivatives thereof, more preferably latanoprost, acid free latanoprost, 15-keto-latanoprost, latanoprost nitroxide, unoprostone, bimatoprost, travoprost, tafluprost and other derivatives without limitations.
According to an embodiment the concentration of the prostaglandin in the composition is comprised between 0.0001 and 0.005% weight/weight.
According to another embodiment the composition is unpreserved.
According to an embodiment, the composition is stable at room temperature.
According to another embodiment the composition is preserved by soft preservatives. Soft preservatives may be sorbic acid, boric acid, EDTA, zinc sulphate, sodium perborate, purite, or polyhexamethylene biguanide.
The ophthalmic composition may contain antioxidants (ascorbic acid, vitamin E, EDTA).
According to an embodiment, the composition of the invention is sterile. According to a preferred embodiment, the composition of the invention is sterilized by heat or filtration.
According to an embodiment the composition is hypoosmotic.
The composition may be a combination of prostaglandin F2alpha or analogues, and derivatives thereof, with thickening and/or moisturizing agents such as polymers used for the relief of dry eye syndrome such as for example polyvinyl alcohol, dextran, polycarbophil, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, povidone, PEG-400, carbopols, hypromellose, polysorbate 80, hydroxypropyl guar, hyaluronic acid, chitosan, dextran and others without limitation. These polymers may be added alone or with other ones in the composition.
The composition may be combined with osmoprotectants such as for example glycerol, dextrose, propylene glycol, glutamate, choline, N-acetyl aspartate, glycine, betaine, trehalose, proline, L-carnitine, sarcosine, asparagine, glycine, dimethylglycine, taurine, beta-alanine, erythritol, glucose and maltose. The composition may have one or more osmoprotectants.
The composition may also be combined with other healing agents such as for example acetylcysteine, vitamins A, D, E and K, lutein, aloe vera extract such as aloine, cyanocobalamine and derivatives.
The composition may be combined with other agents which may stop infections or activate the epithelial growth factor, i.e. secretagogue agents such as for example 15(S)-HETE, prostaglandins E and Flalpha, or anti-inflammatory agents which may help healing lesions by a mechanism of action complementary to F2alpha prostaglandins. Those agents may be antibiotics such as for example chloramphenicol, ciprofloxacin, gentamycin, erythromycin, vancomycine, imipeneme, sulfadiazine; antifungals such as for example amphotericin B, ketoconazole, econazole, fluconazole, iconazole; antivirals such as for example idoxuridine, acyclovir, ganciclovir, cidofovir, interferon, DDI, AZT, foscarnet, vidarabine; anti-inflammatories such as for example non-steroidal anti-inflammatories such as for example salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam or steroidal therapeutic agent including but not limited to beclomethasone, betamethasone, corticosterone, cortisone, dexamethasone, dexamethasone palmitate, difluprednate, flumethasone, fluocinolone acetonide, prednisolone, prednisone, rimexolone, tixocortol, triamcinolone and analogues, derivatives, prodrugs, salts and lipophilic esters thereof, prostaglandin E2 derivatives.
In another embodiment, the therapeutic agent may be combined with a healing agent including but not limited to vitamin A, vitamin E, vitamin D and vitamin K, alpha-tocopherol derivatives, retinol derivatives, lutein, aloe vera extracts such as for example aloine, omega-3 fatty acids, cyanocobalamin, L-cystine, pyridoxine, acetylcysteine, essential oils such as for example oil of calendula, cedar, lavender and their analogues and derivatives thereof.
According to an embodiment the composition may be buffered to maintain the pH stable by including appropriate buffers such as for example phosphate or borate buffers.
The composition of the invention may comprise thickening agents and/or moisturizing agents.
According to an embodiment the composition is packaged in single use vials, multidose droppers or preservative-free multidose droppers.
Method of Use
Another object of this invention is a method for treating surface ocular conditions, comprising administration to a patient in need thereof, a composition of the invention as described above, the therapeutic amount of prostaglandin F2 alpha in the composition preferably ranging from 0.0001 to 0.005% in weight to the weight of the total composition. In this embodiment, the composition of the invention is preferably administered at least once per day, with a maximum of four instillations per day.
Another object of this invention is a method for treating surface ocular conditions, preferably corneal and/or conjunctival lesions, comprising administration to a patient in need thereof, a composition of the invention, i.e. a composition comprising a therapeutic amount of a prostaglandin F2alpha or analogue, or derivative thereof. In a preferred embodiment, in the method of the invention,the therapeutic amount of prostaglandin F2alpha or analogue, or derivative thereof in the composition ranges from 0.0001 to 0.005% in weight to the weight of the total composition. Advantageously, the composition used in the method of the invention is free of deleterious preservative. In an embodiment, the prostaglandin F2alpha analogue is selected from the group consisting of latanoprost, acid free latanoprost, 15-keto-latanoprost, latanoprost nitroxide unoprostone, bimatoprost, travoprost, tafluprost. According to an embodiment, the composition is an aqueous solution, a viscous or semi-viscous gel, a suspension, a solid insert or an anionic or cationic emulsion. Preferably, the composition is in the form of eye drops, artificial tears, gel or ointment. The composition used in the method of the invention may be isoosmotic or hypoosmotic. The composition may further comprise osmoprotectants, or other healing agents, buffers, thickening agents, moisturizing agents and antioxidants agents. The composition of the invention, as used in the method, may be unpreserved, preservative-free, self-preserved or preserved with soft preservatives. According to the method of the invention, the composition may be administered at least once per day, with a maximum of four instillations per day. In an embodiment, the composition is administered during three to five days. According to the method of the invention, the composition may further comprise an anti-glaucoma agent, an anti-inflammatory agent, an antibiotic, an antiviral or an antifungal, and other secretagogue compounds.
According to a first embodiment, the patient is not affected by glaucoma. In this embodiment, the therapeutic amount of prostaglandin F2 alpha, preferably latanoprost in the composition of the invention, preferably ranges from 0.0001 to 0.004% or to less than 0.004%, preferably from 0.0005 to 0.002% in weight to the weight of the total composition; in this embodiment, preferably, the composition is administered during three to five days.
According to a second embodiment, the patient is affected by glaucoma. In this embodiment, the therapeutic amount of prostaglandin F2 alpha, preferably latanoprost, in the composition of the invention preferably ranges from 0.004 to 0.005% or from more than 0.004 to less than 0.005% in weight to the weight of the total composition. In this indication, the dose regimen preferably is one drop per day.
Manufacturing Process
Aqueous Solution
Prostaglandin is put at the adequate concentration in water and mixed by magnetic stirring. If the prostaglandin has difficulties to solubilise, the solution may be submitted 10 minutes to a high shear mixer. Also to help the solubilisation, a surfactant or a co-solvent may be added or the solution may be slightly heated to 50° C.
Emulsion
The emulsions of the invention are prepared according to the following steps:                preparation of the oily phase by mixing the prostaglandin with a saturated oil (such as for example MCT),        preparation of the aqueous phase by mixing the water-soluble ingredients (osmoprotectant agent, viscosifying agent, buffers) with purified water;        incorporating the oily phase to the aqueous phase;        rapidly heating the coarse emulsion obtained, preferably at 75° C.;        decreasing the emulsion droplet size by any suitable means known to the man skilled in the art, for example by shear mixing;        cooling down the emulsion preferably to about 20° C. using an ice bath;        homogenizing the cooled emulsion;        optionally, adjusting the pH to a physiological pH, by using for example NaOH or HCl;        optionally sterilizing the emulsion by autoclaving.        